Pexgemon Press
Life Sciancas Vol. 17, pp . 449-454 Printed in the U .S .A .
FETAL AND NEONATAL BREATHING MOVEMENTS IN MAN AFTER BETAMETHASONE Karel S . Marbâl, Gerhard M. Geaaser, and Stea A. V . Ohrlander Department of Obstetrics and Gynecology, University of Lund, Anmässe Sjukhuset, S-214 01 Ms1mö, Sweden (Received in final form June 30, 1975) Summary Nineteen women in the last trimester of pregnancy were treated with betamethasone 12 mg daily for three consecutive days . The fetal breathing movements were monitored by as ultrasonic method before sad after the treatment sad the patterns of movements were compared to those in controls . In seven treated canes the recording of breathing was performed also is the neoaatal period . Betamethasone is the given dose, which causes pronounced alterations in the fetal corticosteroid balance, does not influence the pattern of breathing movements in the fetus sad newborn. Although corticosteroids are known to affect several functions of CNS, the maturation of mechanisms regulating breathing movements in the perinatal period is apparently not accelerated by betamethasoae. Treatment with betamethasane to prevent IRDS, where preterm deliveries are expected, has recently been suggested (1, 2) . The fairly large corticosteroid dose advocated involves a profound, transient alteration of the fetal adrenal function (3) and also influences the estrogen output in the urine of the mother (4) . However, scarce information is available whether other organ systems are affected by prenatal treatment with corticosteroids (5) . Experiments on sheep fetuses suggest that prenatal respiratory movements in utero arc influenced by medullary (6) as well as by cortical (7) impulses . Monitoring of fetal chest movements in man has recently become possible by a noninvasive ultrasonic method (8). To estimate the effect exerted by prenatal corticosteroid administration on the complex physiological system controlling respiratory movements, the fetal and neonatal breathing patterns in humans were studied in connection to treatment with betamethasoae . Materials and Methods Nineteen pregnant women in the 29th - 35th (mean 32 .4) gestational week were classified, in view of clinical signs or previous history, as at risk of pre-term delivery . To induce the synthesis of pulmonary surfactants, the women were treated with betamethasone for three consecutive days . Each day, 6 mg fast-acting betamethasone disodivm phosphate and 6 mg slow449
450
Perinatal eraathinq After Bstamethasone
Vol . 17, No . 3
acting betamethasone acetate (Celestona Bifas~~, Schering Corp . ), equivalent to 600 mg cortisone, were administered . Ten women in the same risk-group, who did not receive nay corticosteroid, served as controls . The gestatioaal age of the controls was 29th - 35th (mean 31 . 9) week . Fetal breathing movements were recorded by ultrasoaography on the day before and the day after the corticosteroid treatment . The recordings were performed continuously for at least 30 min with the patients recumbent in the morning after breakfast. The fetal thoracic movements were followed by an adaptation of the ultrasoaographic technique developed by Boddy and Robinson (8). A transducer was applied to the maternal abdomen d as A-scan picture wan dispiayed on a modified ultrasonoscope (Ekoline 20~, Smith Kline Instr . Inc .), The frequency of the ultrasound was 2 . 25 MHz emitted in 1 000 pulses/ sec giving as energy output of 2 mPW/cm 2 . The echo of the fetal thoracic wall was gated and its movements recorded on a polygraph (Grass) together with maternal breathing monitored via a small thermistor applied to one nostril. Breathing movements in the newborns were registered after delivery of the betamethasoae-treated women by measurement of the traasthoracic impedance (9) for at least 30 min st the age of 2 h (n=6) and 24 h (a=7), During these recordings the infants were sheltered from light, sound and heat loss, and oaiy records from quiet infants were considered . As controls to this group served 21 healthy infants, born in normal parturition after an uaeveatful pregnancy by moChers not receiving betamethasone . The fetal thoracic movements for each 20 sec period were classified according to Parmelee (10) in regular, irregular, periodic or apneic breathing movements . The relative proportion of time during which fetal chest waü movements of a specific pattern were prsseat, was calculated for the 30 min recording . This classification is different to that used by Boddy and associates (8, il) but a significant correlation (r=0 .69) has been found between the total incidence of fetal breathing movements, measured according to Boddy, and the incidence of apnea plus periodic breathing, measured according to Parmelee (unpublished observation) . Results Table 1 summarizes the fetal breathing movement patterns recorded in the two groups . No significant changes in the pattern distribution occured in the group receiving betamethasoae treatment for three days . A slightiy but significantly lower proportion of periodic and apaeic breathing (p< 0 . 05) in the controls than in the betamethasoae group was present during the first recording. The relative proportion of the various breathing movements was stable between the two recordings with four days interval also in the control group, which, apart from the corticosteroid administration, was subjected to examinations sad treatment similar to the former group. Also after birth no sigaificaat difference is breathing patterns appeared between the betamethasoae group sad the controls (Table 2) ; in both groups a substantial increase in regular breathing eras registered .
Perinatal Breathing After 8etamethasone
Vol . 17, No . 3
451
Table 1 Patters of Fetal Breathing Movements before and after Betamethasoae Administration to the Mother . Mean f SEM . Betamethasone Group Gestational Age at Start of Study : 32 .4 ± 0 . 5 weeks Interval to Parturitioa: 32 ± 4 days Breathing Movements
One day before corticosteroid (Day 0} n=19 One day after corticosteroid (Day +4) n=19 2-8 days after corticosteroid n=6 > 8 days after corticosteroid n=6
Regular
Irregular
Periodic
Apneic
0.4 f0 .4
76 . 5 f4 .0
13 .6 t2 .2
9. 5 f2 .1
0.5 f0 .3
75 .8 ß. 7
12 .8 f2 .4
10 .9 f1 .9
3 .8 f3 .3
83 .2 ß.4
7.5 f2 .1
5.5 f1 .8
0.2 t0 .2
83 .7 f6 .1
10 .5 f4 .0
5 .6 f2 .3
-_-_ -_ __ -_ -__-sxexxxxox=s=sxxxsssaaxsaax= ===aaxox=====_-_-_-_-_-__xsssxx -_-_-_-_-_-_-___
Control Group
Gestational Age at Start of Study: 31 .9 f 0. 7 weeks Interval to Parturition: 38 f 7 days Breathiag Movements Regular
Irregular
Periodic
Apneic
Day 0 n=10
0.4 f0 .2
87 .9 f2 .8
7. 1 fi .6
4.6 t1 .4
Day +4 n=30
0. 1 ±0 . i
89 .9 ±2 . 5
6 .6 fi .9
3.4 f0 .8
Discussion Treatment with betamethasone before birth to prevent IRDS involves the possible hazards of affecting the adrenal function of the newborn and of undesired enzyme induction in organs other thaw the fetal lungs . No adverse effects ascribable to this therapy have bees documented (see 5) and the therapeutic benefits to be gained (i, 2) seem to justify a cautious use of this treatment . The interdependence of the nervous and hormonal systems is well established . Corticosteroids exert important influences on the central nervous sys-
452
Perinatal Hreathinq After Hatamethasone
Vol . 17, No . 3
Table 2 Breathing Patterns in Newborns . Mean f SEM . Betamethasone Group Postconceptional Age : 37 . 5 t 0 . 5 weeks Interval after Start of Treatment: 26 f 4 days Breathing Movements
2 h after birth n=6
Regular
Irregular
Periodic
Apneic
20 . 0 f8 .3
70 . T t7 .2
4. 9 f1 .2
4.4 f1 .8
24 h after birth 31 . 0 61 .4 4. 0 3.6 a=7 f10 .7 f10.5 f2 .0 f1 .2 __ .----=-_ =av= ===x==== -_----= =s =====______-___--_-_______------ _==--=v===-_____-- ____Control Group Postcoaceptional Age: 39 .8 t 0.2 weeks Breathing Movements Regular
Irregular
Periodic
Apneic
2 h after birth n=18
19 .2 f4 .5
68 .3 f4 .6
7. 7 f2 .8
4.8 f2 .2
24 h after birth n=21
31 .0 f4 .5
58 . 5 ß .9
6 .3 f1 .4
4.2 f0 .8
tem ae evidenced by changes in psyche, EEG and cerebral excitability (12) . The mechanisms by which the corticosteroids affect the central nervous system are not completely known but influences on the cerebral blood-flow and on the electrolyte balance are thought to be important (13) . Brain catecholamines might also act as mediators in the corticosteroid effect on the ceatrsl nervous system : the pituitary-adrenal system plays a role in the regulation of the amine turnover in ascending central catecholamiaergic neurons (14), and betamethasone has been demonstrated to produce both acute and chronic changes in the brain monoamine content (15) . The pioneer work of Dawee and associates (7) revealed that breathing movements in fetal Iambs are associated with certain states of central nervous system activity . Thus fetal breathing periods coincide with periods of fetal REM-sleep concomitant with fast and low voltage in EEG. This cerebral dependency is also indirectly evidenced by the finding that general anesthesia and hypoglycemia arrested the fetal breathing movements (7). The corticosteroid dose administered to the women is the present study is substantial and has recently been shown to lower the cortisol level in the maternal plasma to 10 % (4) and in the amniotic fluid to 22 % of the basal
Vol . 17, No . 3
Perinatal Breathing After Betamethasone
453
values (3) . Despite this effect on the adrenals, the fetal breathing movements were unaffected, which, in view of the hypothesis that corticosteroids exert their effect on the central nervous system by disturbing the electrolyte balance (13), might partly be explained by the fact that betamethasoae is essentially devoid of mineralocorticoid activity (16) . Ia fetal sheep, a reciprocal correlation was recently found between the incidence of fetal breathing movements and the fetal plasma ACTH concentration; there was ao correlation of breathing movements with the plasma corticosteroid concentration (11) . Although indirect evidence suggests that betamethasane given to pregnant women blocks the release of fetal ACTH (Ohrlander, Gennser, Nilsson, and Eneroth, to be published) we have not made actual measurements of the fetal peptide ; this leaves the question of a epeciea difference unanswered . Corticosteroid therapy accelerates the synthesis of pulmonary surfactants in the fetus (17) and profoundly changes the pressure-volume relationship and the distensibility of the non-aerated lung (18) . The present results demonstrate that the fetal chest movements are not measurably influenced by altered physical properties in the respiratory tract, which is in concordance with a concept that fetal breathing movements are predominantly an expression of their central nervous regulation . Aclgiowled ¢emeat This work was supported by grants from the Swedish Medical Research Council (B75-17X-4517-OS), the Maltaus Bergwall Foundation, snd Prenatalforskaing ofonden. References 1. 2.
G. C. LIGGINS and R. N . HOWIE, Pediatrics 50 515-525 (1972) . R. N. HOWIE and G. C . LIGGINS, Restwratorv Dietresa Svndromé . C . A. VILLEE, D, B. VILLEE, and I. ZUCKERMAN (ede . ), pp . 369 380, Acad . Press, New York and London (1973) . 3 . G. GENNSER, S. OHRLANDER, and P. ENEROTH, Am . J. Obstet . Gynec . , in press (1975) . 4 . S . OHRLANDER, G. GENNSER, and L. GRENNERT, Am . J . Obstet . Gyaec ., in press (1975) . 5 . M . E . AVERY, Brit . Med. Bull . 31 13-17 (1975) . 6, E, BYSTRZYCKA, B . S. NAIL, and M. J. PURVES, J. Physiol. 236 36 P (1973) . 7. G. S . DAWES, Foet and Neonatal Phvsiolo¢v (Proceedings of The Sir Joseph Barcroft Centenary Symposium), R . S . COMLINE, K. W . CROSS, G. S . DAWES, and P. W. NATHANIELSZ (eds . ), pp . 49-62, Cambridge University Press, London (1973) . 8 . K. BODDY and J. S . ROBINSON, Lancet 2 1231-1233 (1971) . 9. T . OLSSON and L. VICTORIN, Acta Paed . Scaad. Suvvl. 207 1-90 (1970) . 10 . A. H. PARMELEE, E. STERN, and M . A. HARRIS, Neuropltdiatrie 3 294-304 (1972) . 11 . K. BODDY, C . T . JONES, and J. S. ROBINSON, Nature ~Q 75-76 (1974) . 12 . G. C. QUARTON, L. D. CLARK, S. COBB, and W . BAUER, Medicine
454
Perinatal Hreathinq Alter Hetapthasone
Vol . 17, tao . 3
(Balt. ) ~ 13-50 (1955) . 13 . D . M. WOODBURY, $ . g9X. 10 275-357 (1958) . 14 . G. R . VAN LOON, Frontiers is Neuroeadocroaolo~y , W . F. GANONG and L. MARTII~TI (eds . ), pp " 209-247, Ozford Uaiv . Press, New York (1973) . 15 . A. F. DE SCHAEPDRYVER, P. PREZIOSI, and U. SCAPAGNINI, Brit . ,Z, Pharmacol. ~460-467 (1969) . 16 . G . SAYERS and R. H. TRAVIS, The Pharmacolo¢ical Basis of TheraS. GOODMAN and A. GILMAN (eds . ), p. 1629, Mac Millaa, ep utics , L. Loadoa and Toronto (1970) . 17 . R . A. DELEMOS, D. W . SHERMETA, J. H. KNELSON, R . KOTAS, and M. E. AVERY, Am . Rev. Resy . Dis. 10 2 459-461 (1970) . 18 . R . V. KOTAS and E. AVERY, J. App. Phvsiol. 30 358-361 (1971) .
M.
Life Sciancas Vol. 17, pp . 449-454 Printed in the U .S .A .
FETAL AND NEONATAL BREATHING MOVEMENTS IN MAN AFTER BETAMETHASONE Karel S . Marbâl, Gerhard M. Geaaser, and Stea A. V . Ohrlander Department of Obstetrics and Gynecology, University of Lund, Anmässe Sjukhuset, S-214 01 Ms1mö, Sweden (Received in final form June 30, 1975) Summary Nineteen women in the last trimester of pregnancy were treated with betamethasone 12 mg daily for three consecutive days . The fetal breathing movements were monitored by as ultrasonic method before sad after the treatment sad the patterns of movements were compared to those in controls . In seven treated canes the recording of breathing was performed also is the neoaatal period . Betamethasone is the given dose, which causes pronounced alterations in the fetal corticosteroid balance, does not influence the pattern of breathing movements in the fetus sad newborn. Although corticosteroids are known to affect several functions of CNS, the maturation of mechanisms regulating breathing movements in the perinatal period is apparently not accelerated by betamethasoae. Treatment with betamethasane to prevent IRDS, where preterm deliveries are expected, has recently been suggested (1, 2) . The fairly large corticosteroid dose advocated involves a profound, transient alteration of the fetal adrenal function (3) and also influences the estrogen output in the urine of the mother (4) . However, scarce information is available whether other organ systems are affected by prenatal treatment with corticosteroids (5) . Experiments on sheep fetuses suggest that prenatal respiratory movements in utero arc influenced by medullary (6) as well as by cortical (7) impulses . Monitoring of fetal chest movements in man has recently become possible by a noninvasive ultrasonic method (8). To estimate the effect exerted by prenatal corticosteroid administration on the complex physiological system controlling respiratory movements, the fetal and neonatal breathing patterns in humans were studied in connection to treatment with betamethasoae . Materials and Methods Nineteen pregnant women in the 29th - 35th (mean 32 .4) gestational week were classified, in view of clinical signs or previous history, as at risk of pre-term delivery . To induce the synthesis of pulmonary surfactants, the women were treated with betamethasone for three consecutive days . Each day, 6 mg fast-acting betamethasone disodivm phosphate and 6 mg slow449
450
Perinatal eraathinq After Bstamethasone
Vol . 17, No . 3
acting betamethasone acetate (Celestona Bifas~~, Schering Corp . ), equivalent to 600 mg cortisone, were administered . Ten women in the same risk-group, who did not receive nay corticosteroid, served as controls . The gestatioaal age of the controls was 29th - 35th (mean 31 . 9) week . Fetal breathing movements were recorded by ultrasoaography on the day before and the day after the corticosteroid treatment . The recordings were performed continuously for at least 30 min with the patients recumbent in the morning after breakfast. The fetal thoracic movements were followed by an adaptation of the ultrasoaographic technique developed by Boddy and Robinson (8). A transducer was applied to the maternal abdomen d as A-scan picture wan dispiayed on a modified ultrasonoscope (Ekoline 20~, Smith Kline Instr . Inc .), The frequency of the ultrasound was 2 . 25 MHz emitted in 1 000 pulses/ sec giving as energy output of 2 mPW/cm 2 . The echo of the fetal thoracic wall was gated and its movements recorded on a polygraph (Grass) together with maternal breathing monitored via a small thermistor applied to one nostril. Breathing movements in the newborns were registered after delivery of the betamethasoae-treated women by measurement of the traasthoracic impedance (9) for at least 30 min st the age of 2 h (n=6) and 24 h (a=7), During these recordings the infants were sheltered from light, sound and heat loss, and oaiy records from quiet infants were considered . As controls to this group served 21 healthy infants, born in normal parturition after an uaeveatful pregnancy by moChers not receiving betamethasone . The fetal thoracic movements for each 20 sec period were classified according to Parmelee (10) in regular, irregular, periodic or apneic breathing movements . The relative proportion of time during which fetal chest waü movements of a specific pattern were prsseat, was calculated for the 30 min recording . This classification is different to that used by Boddy and associates (8, il) but a significant correlation (r=0 .69) has been found between the total incidence of fetal breathing movements, measured according to Boddy, and the incidence of apnea plus periodic breathing, measured according to Parmelee (unpublished observation) . Results Table 1 summarizes the fetal breathing movement patterns recorded in the two groups . No significant changes in the pattern distribution occured in the group receiving betamethasoae treatment for three days . A slightiy but significantly lower proportion of periodic and apaeic breathing (p< 0 . 05) in the controls than in the betamethasoae group was present during the first recording. The relative proportion of the various breathing movements was stable between the two recordings with four days interval also in the control group, which, apart from the corticosteroid administration, was subjected to examinations sad treatment similar to the former group. Also after birth no sigaificaat difference is breathing patterns appeared between the betamethasoae group sad the controls (Table 2) ; in both groups a substantial increase in regular breathing eras registered .
Perinatal Breathing After 8etamethasone
Vol . 17, No . 3
451
Table 1 Patters of Fetal Breathing Movements before and after Betamethasoae Administration to the Mother . Mean f SEM . Betamethasone Group Gestational Age at Start of Study : 32 .4 ± 0 . 5 weeks Interval to Parturitioa: 32 ± 4 days Breathing Movements
One day before corticosteroid (Day 0} n=19 One day after corticosteroid (Day +4) n=19 2-8 days after corticosteroid n=6 > 8 days after corticosteroid n=6
Regular
Irregular
Periodic
Apneic
0.4 f0 .4
76 . 5 f4 .0
13 .6 t2 .2
9. 5 f2 .1
0.5 f0 .3
75 .8 ß. 7
12 .8 f2 .4
10 .9 f1 .9
3 .8 f3 .3
83 .2 ß.4
7.5 f2 .1
5.5 f1 .8
0.2 t0 .2
83 .7 f6 .1
10 .5 f4 .0
5 .6 f2 .3
-_-_ -_ __ -_ -__-sxexxxxox=s=sxxxsssaaxsaax= ===aaxox=====_-_-_-_-_-__xsssxx -_-_-_-_-_-_-___
Control Group
Gestational Age at Start of Study: 31 .9 f 0. 7 weeks Interval to Parturition: 38 f 7 days Breathiag Movements Regular
Irregular
Periodic
Apneic
Day 0 n=10
0.4 f0 .2
87 .9 f2 .8
7. 1 fi .6
4.6 t1 .4
Day +4 n=30
0. 1 ±0 . i
89 .9 ±2 . 5
6 .6 fi .9
3.4 f0 .8
Discussion Treatment with betamethasone before birth to prevent IRDS involves the possible hazards of affecting the adrenal function of the newborn and of undesired enzyme induction in organs other thaw the fetal lungs . No adverse effects ascribable to this therapy have bees documented (see 5) and the therapeutic benefits to be gained (i, 2) seem to justify a cautious use of this treatment . The interdependence of the nervous and hormonal systems is well established . Corticosteroids exert important influences on the central nervous sys-
452
Perinatal Hreathinq After Hatamethasone
Vol . 17, No . 3
Table 2 Breathing Patterns in Newborns . Mean f SEM . Betamethasone Group Postconceptional Age : 37 . 5 t 0 . 5 weeks Interval after Start of Treatment: 26 f 4 days Breathing Movements
2 h after birth n=6
Regular
Irregular
Periodic
Apneic
20 . 0 f8 .3
70 . T t7 .2
4. 9 f1 .2
4.4 f1 .8
24 h after birth 31 . 0 61 .4 4. 0 3.6 a=7 f10 .7 f10.5 f2 .0 f1 .2 __ .----=-_ =av= ===x==== -_----= =s =====______-___--_-_______------ _==--=v===-_____-- ____Control Group Postcoaceptional Age: 39 .8 t 0.2 weeks Breathing Movements Regular
Irregular
Periodic
Apneic
2 h after birth n=18
19 .2 f4 .5
68 .3 f4 .6
7. 7 f2 .8
4.8 f2 .2
24 h after birth n=21
31 .0 f4 .5
58 . 5 ß .9
6 .3 f1 .4
4.2 f0 .8
tem ae evidenced by changes in psyche, EEG and cerebral excitability (12) . The mechanisms by which the corticosteroids affect the central nervous system are not completely known but influences on the cerebral blood-flow and on the electrolyte balance are thought to be important (13) . Brain catecholamines might also act as mediators in the corticosteroid effect on the ceatrsl nervous system : the pituitary-adrenal system plays a role in the regulation of the amine turnover in ascending central catecholamiaergic neurons (14), and betamethasone has been demonstrated to produce both acute and chronic changes in the brain monoamine content (15) . The pioneer work of Dawee and associates (7) revealed that breathing movements in fetal Iambs are associated with certain states of central nervous system activity . Thus fetal breathing periods coincide with periods of fetal REM-sleep concomitant with fast and low voltage in EEG. This cerebral dependency is also indirectly evidenced by the finding that general anesthesia and hypoglycemia arrested the fetal breathing movements (7). The corticosteroid dose administered to the women is the present study is substantial and has recently been shown to lower the cortisol level in the maternal plasma to 10 % (4) and in the amniotic fluid to 22 % of the basal
Vol . 17, No . 3
Perinatal Breathing After Betamethasone
453
values (3) . Despite this effect on the adrenals, the fetal breathing movements were unaffected, which, in view of the hypothesis that corticosteroids exert their effect on the central nervous system by disturbing the electrolyte balance (13), might partly be explained by the fact that betamethasoae is essentially devoid of mineralocorticoid activity (16) . Ia fetal sheep, a reciprocal correlation was recently found between the incidence of fetal breathing movements and the fetal plasma ACTH concentration; there was ao correlation of breathing movements with the plasma corticosteroid concentration (11) . Although indirect evidence suggests that betamethasane given to pregnant women blocks the release of fetal ACTH (Ohrlander, Gennser, Nilsson, and Eneroth, to be published) we have not made actual measurements of the fetal peptide ; this leaves the question of a epeciea difference unanswered . Corticosteroid therapy accelerates the synthesis of pulmonary surfactants in the fetus (17) and profoundly changes the pressure-volume relationship and the distensibility of the non-aerated lung (18) . The present results demonstrate that the fetal chest movements are not measurably influenced by altered physical properties in the respiratory tract, which is in concordance with a concept that fetal breathing movements are predominantly an expression of their central nervous regulation . Aclgiowled ¢emeat This work was supported by grants from the Swedish Medical Research Council (B75-17X-4517-OS), the Maltaus Bergwall Foundation, snd Prenatalforskaing ofonden. References 1. 2.
G. C. LIGGINS and R. N . HOWIE, Pediatrics 50 515-525 (1972) . R. N. HOWIE and G. C . LIGGINS, Restwratorv Dietresa Svndromé . C . A. VILLEE, D, B. VILLEE, and I. ZUCKERMAN (ede . ), pp . 369 380, Acad . Press, New York and London (1973) . 3 . G. GENNSER, S. OHRLANDER, and P. ENEROTH, Am . J. Obstet . Gynec . , in press (1975) . 4 . S . OHRLANDER, G. GENNSER, and L. GRENNERT, Am . J . Obstet . Gyaec ., in press (1975) . 5 . M . E . AVERY, Brit . Med. Bull . 31 13-17 (1975) . 6, E, BYSTRZYCKA, B . S. NAIL, and M. J. PURVES, J. Physiol. 236 36 P (1973) . 7. G. S . DAWES, Foet and Neonatal Phvsiolo¢v (Proceedings of The Sir Joseph Barcroft Centenary Symposium), R . S . COMLINE, K. W . CROSS, G. S . DAWES, and P. W. NATHANIELSZ (eds . ), pp . 49-62, Cambridge University Press, London (1973) . 8 . K. BODDY and J. S . ROBINSON, Lancet 2 1231-1233 (1971) . 9. T . OLSSON and L. VICTORIN, Acta Paed . Scaad. Suvvl. 207 1-90 (1970) . 10 . A. H. PARMELEE, E. STERN, and M . A. HARRIS, Neuropltdiatrie 3 294-304 (1972) . 11 . K. BODDY, C . T . JONES, and J. S. ROBINSON, Nature ~Q 75-76 (1974) . 12 . G. C. QUARTON, L. D. CLARK, S. COBB, and W . BAUER, Medicine
454
Perinatal Hreathinq Alter Hetapthasone
Vol . 17, tao . 3
(Balt. ) ~ 13-50 (1955) . 13 . D . M. WOODBURY, $ . g9X. 10 275-357 (1958) . 14 . G. R . VAN LOON, Frontiers is Neuroeadocroaolo~y , W . F. GANONG and L. MARTII~TI (eds . ), pp " 209-247, Ozford Uaiv . Press, New York (1973) . 15 . A. F. DE SCHAEPDRYVER, P. PREZIOSI, and U. SCAPAGNINI, Brit . ,Z, Pharmacol. ~460-467 (1969) . 16 . G . SAYERS and R. H. TRAVIS, The Pharmacolo¢ical Basis of TheraS. GOODMAN and A. GILMAN (eds . ), p. 1629, Mac Millaa, ep utics , L. Loadoa and Toronto (1970) . 17 . R . A. DELEMOS, D. W . SHERMETA, J. H. KNELSON, R . KOTAS, and M. E. AVERY, Am . Rev. Resy . Dis. 10 2 459-461 (1970) . 18 . R . V. KOTAS and E. AVERY, J. App. Phvsiol. 30 358-361 (1971) .
M.
